Stable preparation comprising anti-pcsk9 antibody

Abstract

The present invention provides a highly concentrated liquid formulation comprising an anti-PCSK9 (human proprotein convertase subtilisin/kexin 9) antibody. The formulation further comprises a buffer, a stabilizer and a surfactant. The liquid formulation disclosed has low viscosity, and the antibody is highly stable after several months of storage.

1 . A stable antibody formulation comprising:
 (a) a buffer;   (b) a stabilizer; and   (c) an antibody or an antigen-binding fragment thereof that specifically binds to human PCSK9, wherein the antibody or the antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein:   HCDR1 has an amino acid sequence of SEQ ID NO: 1;   HCDR2 has an amino acid sequence of SEQ ID NO: 2;   HCDR3 has an amino acid sequence of SEQ ID NO: 3;   LCDR1 has an amino acid sequence of SEQ ID NO: 4;   LCDR2 has an amino acid sequence of SEQ ID NO: 5; and   LCDR3 has an amino acid sequence of SEQ ID NO: 6; and   the pH of the formulation is 5.5-6.5.   
     
     
         2 . The antibody formulation according to  claim 1 , wherein the buffer is an acetate buffer or a histidine buffer. 
     
     
         3 . The antibody formulation according to  claim 2 , wherein the buffer is a histidine buffer prepared by L-histidine and L-histidine monohydrochloride. 
     
     
         4 . The antibody formulation according to  claim 2 , wherein the histidine buffer comprises histidine at 1-10 mM and a histidine salt at 10-20 mM. 
     
     
         5 . The antibody formulation according to  claim 1 , wherein the concentration of the buffer is 15-25 mM. 
     
     
         6 . The antibody formulation according to  claim 1 , wherein the stabilizer is arginine or a salt thereof, sorbitol, mannitol or sucrose, or a combination of arginine or a salt thereof and sorbitol, mannitol or sucrose. 
     
     
         7 . The antibody formulation according to  claim 8 , wherein the stabilizer is an arginine salt at 50-200 mM in the formulation; or the stabilizer is a mixture of an arginine salt and mannitol or sorbitol, wherein the concentration of the arginine salt in the formulation is 50-150 mM, the concentration of mannitol or sorbitol is 50-200 mM, and the total concentration of the two stabilizers is in the range of 50-250 mM. 
     
     
         8 . The antibody formulation according to  claim 1 , wherein the antibody or the antigen-binding fragment thereof comprises a heavy chain variable region (VH) having an amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) having an amino acid sequence of SEQ ID NO: 8. 
     
     
         9 . The antibody formulation according to  claim 1 , wherein the antibody or the antigen-binding fragment thereof comprises a heavy chain (HC) having an amino acid sequence of SEQ ID NO: 9 and a light chain (LC) having an amino acid sequence of SEQ ID NO: 10. 
     
     
         10 . The antibody formulation according to  claim 1 , wherein the antibody formulation further comprises polysorbate 20 or polysorbate 80 at about 0.01% to about 0.05%. 
     
     
         11 . The antibody formulation according to  claim 1 , comprising:
 (a) a histidine buffer at about 20 mM;   (b) an arginine salt at about 100-200 mM;   (c) polysorbate 20 at about 0.02%; and   (d) the antibody or the antigen-binding fragment that specifically binds to human PCSK9 at about 100 mg/mL to about 200 mg/mL.   
     
     
         12 . The antibody formulation according to  claim 1 , wherein the antibody formulation is selected from antibody formulations comprising:
 (A) (1) the anti-PCSK9 antibody or the antigen-binding fragment thereof at about 100 mg/mL to about 200 mg/mL; (2) a histidine buffer at about 10-50 mM, about pH 5.5-6.5; (3) an arginine salt at about 50 mM to about 200 mM; and (4) a nonionic surfactant at about 0% to about 0.1%;   (B) (1) the anti-PCSK9 antibody or the antigen-binding fragment thereof at about 150±10 mg/mL; (2) a histidine buffer at about 20 mM, about pH 5.5-6.5; (3) an arginine salt at about 60±5 mM, 130±5 mM or 160±5 mM; and (4) a nonionic surfactant at about 0% to about 0.1%;   (C) (1) the anti-PCSK9 antibody or the antigen-binding fragment thereof at about 150±10 mg/mL, wherein the antibody comprises a heavy chain variable region (VH) having an amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) having an amino acid sequence of SEQ ID NO: 8; (2) a histidine buffer at about 20 mM, about pH 5.5-6.5; (3) arginine at about 160±5 mM; and (4) polysorbate 20 at about 0.02%;   (D) (1) the anti-PCSK9 antibody or the antigen-binding fragment thereof at about 150±10 mg/mL, wherein the antibody is a full-length antibody comprising a heavy chain having an amino acid sequence of SEQ ID NO: 9 and a light chain having an amino acid sequence of SEQ ID NO: 10; (2) a histidine buffer at about 20 mM, about pH 5.5-6.5; (3) arginine at about 160±5 mM; and (4) polysorbate 20 at about 0.02%;   (E) (1) the anti-PCSK9 antibody or the antigen-binding fragment thereof at 150 mg/mL; (2) a histidine buffer at 20 mM; (3) arginine hydrochloride at 160 mM; and (4) polysorbate 20 at 0.02%;   (F) (1) the anti-PCSK9 antibody or the antigen-binding fragment thereof at 150 mg/mL; (2) a histidine buffer at 20 mM; (3) arginine hydrochloride at 120 mM and mannitol at 60 mM; and (4) polysorbate 20 at 0.02%; or   (G) (1) the anti-PCSK9 antibody or the antigen-binding fragment thereof at 150 mg/mL; (2) a histidine buffer at 20 mM; (3) arginine hydrochloride at 60 mM and mannitol at 160 mM; and (4) polysorbate 20 at 0.02%.   
     
     
         13 . A delivery device comprising the antibody formulation according to  claim 1 . 
     
     
         14 . A pre-filled syringe comprising the antibody formulation according to  claim 1 . 
     
     
         15 . (canceled) 
     
     
         16 . The antibody formulation according to  claim 4 , wherein the molar ratio of histidine to the histidine salt is in the range of 1:1-1:4. 
     
     
         17 . The antibody formulation according to  claim 2 , wherein the pH of the buffer is 5.5-6.5. 
     
     
         18 . The antibody formulation according to  claim 6 , wherein the stabilizer is arginine salt, a mixture of arginine salt and mannitol, or a mixture of arginine salt and sorbitol. 
     
     
         19 . The antibody formulation according to  claim 6 , wherein the concentration of the stabilizer is 50-300 mM. 
     
     
         20 . The antibody formulation according to  claim 1 , wherein the concentration of the antibody or the antigen-binding fragment is about 100 mg/mL to about 200 mg/mL. 
     
     
         21 . A method for treating, preventing or improving any diseases associated with PCSK9 activity, comprising administering to a subject in need of a therapeutically effective amount of the antibody formulation of  claim 1 .